The growth of cells is believed to be maintained in balance (cytostasis) through the opposing actions of the protein products of promotor and suppressor genes (oncogenes). Mutations of the promotor or suppressor genes result in the production of mutated protein products which are incapable of carrying out their normal growth-enhancing or growth-reducing functions. These proteins are not active themselves. Instead, the proteins are activated by (1) phosphorylation with a nucleoside triphosphate, such as ATP or GTP, and one of several kinases, such as protein tyrosine kinase, or (2) autophosphorylation, i.e., phosphorylations catalytically mediated by the protein itself. These phosphorylations generally occur on the hydroxyl group of tyrosine, serine or threonine residues of the proteins. Phosphorylated protein products of mutated genes are incapable of carrying out their normal functions. Inhibiting the phosphorylation of these mutant proteins should help control cell growth.
Protein tyrosine kinases (PTKs) mediate important signaling events associated with cellular activation, differentiation and mitogenesis. See, for example, Smyth et al. “Non-Amine Based Analogues of Lavendustin A as Protein-Tyrosine Kinase Inhibitors,” J. Med. Chem., 36: 3010-3014, 3010 (1993); and Gazit et al. “Tyrphostins. 2. Heterocyclic and α-Substituted Benzylidenemalononitrile Tyrphostins as Potent Inhibitors of EGF Receptor and Erb2/neu Tyrosine Kinases,” J. Med. Chem., 34: 1896-1907, 1896 (1991). The generation of mitogenic signals from abnormally expressed or deregulated protein tyrosine kinases is believed to play an important role in the loss of growth control associated with the neoplastic process. Traxler et. al. “Sulfonylbenzoyl-Nitrostyrenes: Potential Bisubstrate Type Inhibitors of the EGF-Receptor Tyrosine Protein Kinase,” J. Med. Chem., 34: 2328-2337, 2328 (1991).
PTK inhibitors are useful as antiproliferative therapeutics, as well as pharmacological probes of the biochemical roles played by tyrosine phosphorylation. J. Med Chem., 36, supra., at p. 3010. PTK inhibitors also may be useful for treating chronic myelogenous leukemia (CML). Patients with CML frequently have a cytogenetic abnormality (the Philadelphia chromosome) resulting from reciprocal translocation between chromosome 9 and chromosome 22. Kaur et al., “Tyrphostin Induced Growth Inhibition: Correlation with Effect on p210bcr-abl Autokinase Activity in K562 Chronic Myelogenous Leukemia,” Anti-Cancer Drugs, 5: 213-222, 213 (1994). Translocation transfers the c-abl non-receptor protein tyrosine kinase protoncogene from its normal position on chromosome 9 into the bcr gene on chromosome 22. Id. An 8 kb mRNA transcript of the bcr-abl fusion gene is translated into a chimeric bcr-abl fusion protein of 210 kDa (p210bcr-abl) that exhibits constitutive protein tyrosine kinase activity. The normal, untranslocated c-abl protoncogene product has considerably lower constitutive protein tyrosine kinase (PTK) activity than p210bcr-abl. Id. This raises the possibility that specific PTK inhibitors directed at p210bcr-abl could be useful to patients with CML.
Certain tyrphostins, synthetic tyrosine kinase inhibitors, have an antiproliferative mechanism. AG957, for example, appears to induce the formation of covalent adducts involving p210bcr-abl and its associated signaling molecules. Kaur G. and Sausville E., “Altered Physical States of p210bcr-abl in Tyrphostin AG957-Treated K562 Cells,” Anti-Cancer Drugs, 7: 815-824, 816 (1996). AG957 also is an effective inhibitor of T-cell, antigen-originated signal transduction and cell growth in Jurkat T-ALL (actula lymphatic leukemia) cells. AG957 apparently affects tyrosine kinase signalling by inhibiting MAP kinase activations and phosphorylation of p210cbl protoncogene. There are at least four classes of tyrphostins: (1) benzenemalonitrile compounds; (2) S-aryl benzenemalonitrile compounds, (3) bisubstrate quinoline compounds; and (4) lavendustin-A-like compounds. Id. Lavendustin A, 5-[(2,5-dihydroxy-benzyl)-(2-hydroxy-benzyl)-amino]-2-hydroxy-benzoic acid, is shown below as compound 1. Lavendustin A, a trisubstituted amine, is a natural product inhibitor of the epidermal growth factor receptor (EGFR) PTK, a potent protein tyrosine kinase inhibitor first isolated from Streptomyces griseolavendus. Devraj et al.'s “A Versatile Solid Phase Synthesis of Lavendustin A and Certain Biologically Active Analogs,” J. Org. Chem., 61: 26 (1996). An active pharmacophore of lavendustin A consists of a more simplified benzylamine, compound 2. Compound 2 contains the 2,5-dihydroxyphenyl ring of erbstatin, compound 3, as well as the diaryl pattern of piceatannol, compound 4, both of which also are natural product PTK Inhibitors. 
Hydroxylated 2-(5′Salicyl)naphthalenes have been investigated as potential protein tyrosine kinase inhibitors. Smyth et al. “Hydroxylated 2-(5-′Salicyl)naphthalenes as Protein-Tyrosine Kinase Inhibitors,” J. Med. Chem., 36: 3015-3020 (1993). Compound 5 is one example of a hydroxylated 2-(5′-Salicyl)naphthalene made by Smyth et al. But, Smyth et al. concluded that “the resulting salicyl-containing bicyclies exhibited extremely poor inhibitory potency when examined against autophosphorylation of immunoprecipitated p56kL PTK preparations.” Id., Abstract, lines 7-9; p. 3017.
The de novo design of PTK inhibitors has been hampered by the lack of three dimensional information regarding PTKs and the interaction of these inhibitors with enzymes. Burke T., “Protein Tyrosine Kinases: Potential Targets for Anti-cancer Drug Development.” Stem Cells, 12: 1-6, 1 (1994). Burke concluded that significant difficulties were faced b) researchers in this field to develop PTK-inhibitor-based antiproliferatives, primarily because the mechanism of antiproliferative activity is not well understood. Id., at p. 4. This has hampered the development of new PTK-inhibitor-based antiproliferatives. As a result, there still is a need for new PTK-inhibitor-based antiproliferatives useful for treating diseases such as CML.